The salt forms of a compound may be important when the compound is used for pharmaceutical purposes. For example, the solid physical properties of a compound may change from one salt form to another, which may affect its suitability for pharmaceutical use. In addition, different salt forms of a compound can incorporate different types and/or different amounts of impurities. Different salt forms of a compound can vary in chemical stability upon exposure to heat and/or humidity over a period of time.
Ceftolozane is a cephalosporin antibacterial agent, also referred to as CXA-101, FR264205, or by chemical names such as (6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazol-2-ium-2-yl)methyl]-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, and 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazolio}methyl-3-cephem-4-carboxylate. Ceftolozane can be obtained as the sulfate salt form, a compound of formula (VI).

Ceftolozane can be obtained using methods described in U.S. Pat. Nos. 7,129,232 and 7,192,943, as well as Toda et al., “Synthesis and SAR of novel parenteral anti-pseudomonal cephalosporin's: Discovery of FR264205,” Bioorganic & Medicinal Chemistry Letters, 18, 4849-4852 (2008), each of which are incorporated herein by reference in their entirety. These methods are illustrated in FIGS. 1B and 1C.
U.S. Pat. No. 7,129,232 further discloses pharmaceutically acceptable salts, generally, of the cephem compounds provided therein, as well as the sulfate salt of ceftolozane. U.S. Pat. No. 7,129,232 discloses preparation of a crystalline form of ceftolozane sulfate salt obtained by dissolving ceftolozane sulfate in aqueous ethanol and adding seed crystals. The resulting crystalline form is described herein as Example 12 (as a comparison for the instant salt forms).
There remains a need for salt forms of ceftolozane that are not only suitable for use in pharmaceutical development, but that can be produced efficiently and with high purity.
The chemical stability of a compound can vary in response to heat and/or humidity over a period of time. The ability to manufacture stable solid compositions of a compound (i.e., solid compositions wherein the compound is chemically stable) is important, particularly when the compound is used for pharmaceutical purposes. There remains a need for solid compositions of ceftolozane with increased chemical stability.